ClinVar Genomic variation as it relates to human health

The ATP7B c.3182G>A (p.Gly1061Glu) missense variant has been well-documented as a pathogenic variant for Wilson disease in many different populations. Across a selection of available literature, the p.Gly1061Glu variant has been identified in a homozygous state in seven patients, in a compound heterozygous state in six patients, and in a heterozygous state in four patients in whom a second variant was not identified (Curtis et al. 1999; Loudianos et al. 1999; Margarit et al. 2005; Santhosh et al. 2006; Khan et al. 2012; Guggilla et al. 2015). Gupta et al. (2007) also found the p.Gly1061Glu variant on 11% of Wilson disease patient chromosomes in the Indian population. The p.Gly1061Glu variant was absent from 222 controls and is reported at a frequency of 0.00036 in the South Asian population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Gly1061Glu variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

A heterozygous missense variation in exon 14 of the ATP7B gene that results in the amino acid substitution of Glutamic acid for Glycine at codon 1061 was detected. The observed variation c.3182G>A (p.Gly1061Glu) lies in the haloacid dehalogenase-like hydrolase domain of the ATP7B protein and has previously been reported in patients affected with Wilson disease [Roy et al. 2020]. The functional studies showed that this variation causes ATP7B retention in the endoplasmic reticulum, inhibits Cu-transport, and lowers ATP7B protein abundance [Roy et al. 2020]. The variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in silico predictions of the variant is probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT, and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

Found on 11% of Wilson disease patient chromosomes in the Indian population (Gupta et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10502777, 22692182, 25982861, 33083013, 31589614, 24094725, 23430908, 18371106, 26207595, 17634212, 25900946, 17823867, 17264425, 15952988, 30120852, 15024742, 10544227)

The missense variant p.G1061E in ATP7B (NM_000053.3) has been reported previously in multiple patients (Gupta A et al; Santhosh S et al; Guggilla et al). It is a common variant in the Indian population. The p.G1061E variant is observed in 12/30,602 (0.0392%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The p.G1061E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1061 of ATP7B is conserved in all mammalian species. The nucleotide c.3182 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000312383, PMID:10502777). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 10544227). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:30655162). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.928>=0.6, 3CNET: 0.933>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000481). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

PS4, PS3, PM1, PM2, PP3, PP4

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1061 of the ATP7B protein (p.Gly1061Glu). This variant is present in population databases (rs764131178, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10502777, 10544227, 15024742, 17264425, 17823867). ClinVar contains an entry for this variant (Variation ID: 312383). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The p.Gly1061Glu variant has been reported in many individuals with Wilson disease, including at least 3 homozygotes and 7 compound heterozygotes (Curtis 1999, Guggilla 2015, Gupta 2007, Loudianos 1999, Margarit 2005, Santhosh 2006). This variant was identified in 0.03% (12/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a low enough frequency to be consistent with a recessive allele. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP4.

The p.G1061E pathogenic mutation (also known as c.3182G>A), located in coding exon 14 of the ATP7B gene, results from a G to A substitution at nucleotide position 3182. The glycine at codon 1061 is replaced by glutamic acid, an amino acid with similar properties. This mutation is one of three common mutations often found in individuals with Wilson disease from South and East India, but has also been reported in affected individuals from other regions (Gupta A et al. Cell. Mol. Neurobiol., 2007 Dec;27:1023-33; Guggilla SR et al. Gene, 2015 Sep;569:83-7). This mutation has been identified in multiple homozygous and compound heterozygous individuals with Wilson disease (Curtis D et al. Hum. Mutat., 1999;14:304-11; Margarit E et al. Clin. Genet., 2005 Jul;68:61-8; Santhosh S et al. Indian J Gastroenterol, 2006;25:277-82; Gupta A et al. Cell. Mol. Neurobiol., 2007 Dec;27:1023-33; Mukherjee S et al. Parkinsonism Relat. Disord., 2014 Jan;20:75-81; Guggilla SR et al. Gene, 2015 Sep;569:83-7). Another study, in which authors modeled the structural effects of various mutations on the ATP7B gene, showed that this mutation site is sensitive to substitutions (Schushan M et al. Metallomics, 2012 Jul;4:669-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.